Vascular and metabolic diseases are, despite cancer, the leading causes of death in the Western World. Although many different ways of treating vascular and metabolic diseases are known, there is still a need for improved medication. Life-style modifications and drug therapy can decrease and delay the morbidity and mortality associated with these diseases. Diabetes of type 1 is successfully treated with insulin, while insulin treatment is only partially effective in diabetes of type 2. The type 2 diabetes is the most frequent one, particularly in elderly people.
One class of compounds promising in the treatment of type 2 diabetes are compounds derived from thiazolidinedione, so called glitazones. They are sensitizing tissue to insulin, thereby allowing the endogenous insulin to more efficiently lower the glucose level in the bloodstream. Examples of marketed glitazones are rosiglitazone and pioglitazone.
Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. Via modulation of the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue and the liver, pioglitazone reduces insulin resistance in peripheral tissues and the liver resulting ultimately in reduced plasma levels of glucose, insulin and glycosylated haemoglobin (HbA1c). By its effects on lipid metabolism, pioglitazone also decreases the level of triglycerides and increases that of high-density lipoproteins (HDL) without changing low-density lipoproteins (LDL) and total cholesterol in patients lipid disorders.
Pioglitazone is indicated for the oral treatment of diabetes mellitus type 2 (previously known as non-insulin-dependent diabetes mellitus, NIDDM) as monotherapy and in combination with a sulfonylurea, metformin or insulin to optimize glucose control. The treatment effects of pioglitazone on glucose levels (efficacy) are, like with other treatments indicated for type 2 diabetes, best reflected by monitoring its effects on lowering HbA1c levels, which are considered to be reflective for the long-term efficacy of any blood glucose lowering agent.
However, the effectiveness of pioglitazone is not considered sufficient and might be improved without increasing the respective doses of pioglitazone by enhancing its effects on muscular metabolism with novel, thiazolidinedione-based compounds which exhibit additional properties over pioglitazone. Compared to increasing the doses of pioglitazone in case of unsatisfactory effectiveness, such novel compounds may also have a more favourable adverse event profile compared to increasing doses of pioglitazone for the typical side effects such as fluid retention and peripheral oedema. Muscular metabolism can be increased, e.g., by physical activity (exercise) which increases both, glucose utilization by the muscular tissue and muscular insulin sensitivity. Similar effects can, however, also be achieved by increasing perfusion of muscular tissue by increasing peripheral perfusion in the microvasculature and thus more efficient glucose dispersal in the sceletal muscles.
Donation of NO is the typical pharmacological effect of organic nitrates and specifically nitrate esters, such as glyceryl trinitrate (nitroglycerine), isosorbide dinitrate, or pentaerythrityl tetranitrate, which act all as coronary vasodilators and improve symptoms and exercise tolerance in patients with coronary artery disease due to atherosclerosis, who are suffering from angina pectoris and one of the established standard treatments. Most organic nitrates (e.g. mononitrates and trinitrates) are fast acting pharmaceuticals with a relatively short halflife and have the typical disadvantage that patients develop a nitrate tolerance, meaning that part of the pharmacodynamic effect is lost during chronic treatment and a three times daily dosing regimen.
Nitrate esters of drugs in general are described in WO 00/61537. Nitrate salts of drugs including pioglitazone are disclosed in WO 02/30867. Diazeniumdiolate derivatives have recently been recognized as alternatives for nitrates, setting free two molecules of NO under physiological conditions. A diazeniumdiolate derivative of tacrine is described by L. Fang et al., J. Med. Chem. 51, 7666-7669 (2008).